Processes for the preparation of glyoxal-2-oxims

ABSTRACT

Novel derivatives of glyoxal-2-oxim represented by the chemical formula ##STR1## wherein R is hydrogen or a lower alkyl or phenyl group, are provided in accordance with the present invention. These derivatives are prepared by reacting the corresponding isoxazole-5-carbaldehyde with nitromethane in the presence of a metal alkoxide, or the corresponding 5-acetylisoxazole with a nitrate. They have anti-inflammatory and/or analgesic activities.

This is a division, of application Ser. No. 016,281 pending filed Mar.2, 1979.

This invention relates to novel glyoxal-2-oxim derivatives and a processfor the preparation thereof. The glyoxal-2-oxim derivatives of thepresent invention are compounds represented by the formula, ##STR2##wherein R is hydrogen or a lower alkyl or phenyl group. The lower alkylgroup represented by R in the above formula includes methyl, ethyl,propyl and butyl groups. The above compounds of the present inventionare all novel and exhibit pharmacological activities such asanti-inflammatory and/or analgesic activities which appear useful asmedicines.

The compounds represented by formula [I] may be prepared, for example,by reacting a compound of the formula, ##STR3## wherein R is defined asabove, with nitromethane in the presence of an excess of a basiccompound.

The following description is made for detailed explanation of thepresent invention. Above compounds [II] are usually known or may beeasily prepared by any known process [See "Gazz. Chim. Ital.", 73, 99,(1943); "Tetrahedron", 23, 4697, (1967)]. The reaction of compound [II]with nitromethane is usually and advantageously carried out in a solventin the presence of a basic compound. As the basic compound metalalkoxides may be generally employed. The metal of said metal alkoxidesincludes metals such as sodium, potassium, aluminium and magnesium, andsaid alkoxides are lower alkoxides including methoxide, ethoxide,propoxide and butoxide. An appropriate solvent may be used in thereaction unless it affects the reaction, but lower alcohols such asmethanol, ethanol, propanol and butanol may preferably be used. Anappropriate ratio of nitromethane to compound [II] may be selected andit is generally advantageous to use a ratio of 1-2 to 1 on thegram-equivalent basis. Also the ratio of a metal alkoxide to compound[II] used should generally be such that an amount of the metal alkoxideis in excess of compound [II], and the alkoxide is preferably used in anamount as large as 1.1-2.0 equivalents per equivalent of compound [II].

The reaction temperature in the above reaction may freely be decided butgenerally the reaction advantageously proceeds within the temperaturerange of from -20° to 60° C. The resulting metal salt, after or withoutisolation, is then acidified with a mineral acid such as hydrochloricacid, sulfuric acid, or the like to produce compound [I] of the presentinvention, which can be easily isolated by a conventional separatingmeans.

Compound [I] of the present invention may also be prepared by reacting acompound represented by the formula, ##STR4## wherein R is the same asdefined above, with a compound of the formula, R'ONO [IV] wherein R'represents hydrogen or a lower alkyl group. Compounds [III] are usuallypublicly known ones or those readily prepared by any publicly knownprocess. [See, Gazz. Chim. Ital., 70, 676, (1940); Ibid., 72, 155,(1942); Ibid., 73, 99, (1943)]. Also, compounds [IV] are usually knownones, and the lower alkyl group represented by R' includes, for example,methyl, ethyl, propyl, butyl and amyl groups. The reaction betweencompounds [III] and [IV] is usually carried out in a solvent in thepresence or absence of a catalyst. The catalyst which may be employedincludes acidic compounds such as gaseous hydrogen chloride,hydrochloric acid, sulfuric acid and acetic acid, and basic compoundswhich are metal alkoxides such as sodium methoxide, sodium ethoxide,potassium methoxide and potassium ethoxide. The solvents used in thepresent reaction are not particularly limited so far as they do notaffect the reaction, but ethers, lower alcohols, acetic acid and thelike may be preferred. An appropriate ratio of compounds [IV] to [III]may be selected but generally it is advantageous to use 1-3 equivalentsof compound [IV] per equivalent of compound [III]. An appropriatetemperature may also be selected, but the reaction proceeds favorablywithin the temperature range of -10° C. to 50° C. Compounds [I] of thepresent invention having been produced by the above reaction can beisolated by a conventional means.

The particularly preferred compounds of the present invention include(3-methylisoxazole-5-yl)-glyoxal-2-oxim and(3-phenylisoxazole-5-yl)glyoxal-2-oxim. Additionally,(3-ethylisoxazole-5-yl)glyoxal-2-oxim,(3-isopropylisoxazole-5-yl)glyoxal-2-oxim and(3-butylisoxazole-5-yl)glyoxal-2-oxim are also preferable.

In respect to the above first two preferred compounds, biologicalactivity tests have been conducted and the results are shown as below:

    ______________________________________                                                   Kind of Test                                                                             Anti-inflam-                                                                  matory acti- Analgesic                                               Acute    vity         activity                                                toxicity (Carrageenin (Stretching                                Compound     (LD.sub.50)                                                                            edema method)                                                                              method)                                    ______________________________________                                        (3-Methyl-                                                                    isoxazole-5-yl)                                                                            890      83%          50%                                        glyoxal-2-oxim                                                                             mg/kg                                                            (3-Phenyliso-                                                                              1690                                                             xazole-5-yl) mg/kg    56%          75%                                        glyoxal-2-oxim                                                                ______________________________________                                    

TEST METHODS (1) Acute toxity

The compounds to be tested were suspended in 0.5% carboxymethylcellulose solution, and the suspension was orally administrated invariable amounts in response to the weights of dd-strain male micehaving those ranging from 20 to 25 g which were forced to abstain fromfood overnight. They were observed for seven days after saidadministration to seek LD₅₀ values by counting the number of dead mice.

(2) Anti-inflammatory activity (Carrageenin edema method)

The compounds to be tested were suspended in 0.5% carboxymethylcellulose solution, and the suspension was orally administrated in 100mg per kg of Wistarstrain male rats having their weight range of 130 to170 g which were forced to abstain from food overnight. These rats werethen injected subcutaneously into their left hind paws each with 0.1 mlof a physiological NaCl solution having dissolved therein carrageen in1% concentration. After three hours from said injection, the rats werekilled, both hind legs were cut out and promptly weighed. There isassumed as weight of edema a value obtained by deducting a weight ofuntreated hind leg from that of the carrageenin injected hind leg of therat. Inhibition ratio of a sample-administrated group to a control grouphas been sought. The control group was administrated only with 0.5%methyl cellulose solution in the same manner.

(3) Analgesic activity (Acetic acid stretching method)

After the compounds to be tested were orally administrated in 100 mg perkg of ddy-strain mice having their weight range of 20 to 25 g, 0.2 ml of0.7% acetic acid was intra-peritoneally administrated to each animal toobserve stretching symptom thereby having found the inhibition ratio(%).

The compounds of the present invention are suitable for the use of ananti-inflammatory agent and/or an analgesic agent. Clinical dosage ofthese compounds ranges usually from 50 to 1000 mg per day for adult, andpreferably from 100 to 500 mg, which may be administrated two to threetimes a day. Dosage may be appropriately adjusted depending onindividual cases such that patient's condition, age, etc. should beconsidered. Administration is conducted in many forms such asinjections, oral administrative preparations, suppositories (rectaladministrations) and external preparations.

The compounds of the present invention may be used as a pharmaceuticalcomposition by being formulated with any and conventionalpharmaceutically acceptable carrier or vehicle, in conventional manner.

Vehicles which may be used for preparation of oral administrativecomposition such as in tablet, capsule, granule and powder forms includethose generally used in the art such as calcium carbonate, calciumphosphate, starch, sugar, lactose, talc, magnesium sterate, gellatin,polyvinyl pyrrolidone, gum arabic, sorbitol, microcrystalline cellulose,polyethylene glycol, carboxymethyl cellulose, Silica AEA® (SankyoCompany Ltd.), TC-5® (Kyowa Hakko Kogyo Co., Ltd.), shellac, etc. Tabletmay be coated by a method well known in the art. Liquid formulations fororal administration may be in the form of aqueous or oily suspension orsolution, syrup, elixir and the like, and prepared by conventionalmeans. Injectionable formulations may be aqueous or oily suspension orsolution, powdery composition with a filler, and lyophilized preparationwhich are dissolved upon their use, or the like. They may be prepared byconventional means.

The present compounds are also provided as a suppository composition forrectal administration, which may contain pharmaceutically acceptablecarriers well known in the art such as polyethylene glycol, lanolin,cacao butter, Witepsol® (Dynamite Nobel Co.) etc.

External preparation is applied preferably in the form of ointment orcream which may be prepared by conventional processes using ingredientswhich are usually employed.

The following examples illustrate the present invention.

EXAMPLE 1

In 50 ml of ethanol were dissolved 5.5 g of3-methylisoxazole-5-carbaldehyde and 3.3 g of nitromethane. To thesolution was added dropwise a solution of sodium ethoxide in ethanol,which had been prepared from 1.5 g of sodium and 30 ml of ethanol, whilestirring at room temperature. After completion of the dropwise addition,the resultant solution was stirred for a further 3 hrs. at roomtemperature and then ether was added thereto to separate the sodiumsalt. This was dissolved in water, which was followed by acidificationwith hydrochloric acid. The resulting precipitate was filtered off andrecrystallized from chloroform to obtain 5.4 g of(3-methylisoxazole-5-yl)glyoxal-2-oxim having m.p. of 179° C.-180° C.Yield, 70%.

    ______________________________________                                        Elemental Analysis (C.sub.6 H.sub.6 N.sub.2 O.sub.3)                                      C       H         N                                               ______________________________________                                        Calcd. (%)    46.76     3.92      18.18                                       Found (%)     46.59     3.92      17.90                                       ______________________________________                                    

EXAMPLE 2

In 40 ml of ethanol were dissolved 3.5 g of3-phenylisoxazole-5-carbaldehyde and 1.3 g of nitromethane, and thencooled to 0°-5° C. While stirring the solution, a solution of sodiumethoxide in ethanol, which had been prepared from 0.6 g of sodium and 20ml of ethanol, was dropwise added thereto. Stirring was continued for 24hrs. at room temperature after completion of the dropwise addition, andthe resultant solution was thereafter concentrated under reducedpressure. Ether was added thereto to separate the sodium salt, which wasthen dissolved in water. The aqueous solution was acidified withhydrochloric acid and then extracted with ether. The ether extract wasdried over sodium sulfate and then ether was removed by distillation.The residue was recrystallized from chloroform to obtain 2.5 g of(3-phenylisoazole-5-yl) glyoxal-2-oxim having m.p. of 155° C.-157° C.Yield, 59%.

    ______________________________________                                        Elemental Analysis (C.sub.11 H.sub.8 N.sub.2 O.sub.3)                                     C       H         N                                               ______________________________________                                        Calcd. (%)    61.12     3.73      12.96                                       Found (%)     60.82     3.65      12.77                                       ______________________________________                                    

EXAMPLE 3

In 30 ml of ether was dissolved 2.5 g of 5-acetyl-3-methylisoxazole.While gaseous hydrogen chloride was passed through the resultantsolution with stirring, a solution of 4.5 g of amyl nitrite in 10 ml ofether was dropped thereinto. After a further one hour stirring at roomtemperature after completion of said dropwise addition, the resultingprecipitate was isolated by filtration. Recrystallization fromchloroform gave 1.0 g of (3-methylisoxazole-5-yl)glyoxal-2-oxim havingm.p. of 179° C.-180° C. Yield, 27%.

    ______________________________________                                        Elemental Analysis (C.sub.6 H.sub.6 N.sub.2 O.sub.3)                                      C       H         N                                               ______________________________________                                        Calcd. (%)    46.76     3.92      18.18                                       Found (%)     46.57     4.01      18.02                                       ______________________________________                                    

What is claimed is:
 1. A process for the preparation of a glyoxal-2-oximderivative represented by the formula, ##STR5## wherein R representshydrogen, C₁₋₄ alkyl or phenyl, which comprises reacting a compound ofthe formula, ##STR6## wherein R is defined as above, with a compound ofthe formula, R'ONO [IV] wherein R' represents hydrogen or lower alkylselected from the group consisting of methyl, ethyl, propyl, butyl andamyl, at a temperature of -10° C. to 50° C.
 2. A process for thepreparation of a glyoxal-2-oxim derivative represented by the formula,##STR7## wherein R represents hydrogen, C₁₋₄ alkyl or phenyl, whichcomprises reacting a compound of the formula, ##STR8## wherein R isdefined as above, with a compound of the formula, R'ONO [IV] wherein R'represents hydrogen or lower alkyl selected from the group consisting ofmethyl, ethyl, propyl, butyl and amyl, at a temperature of -10° C. to50° C. in the presence of an acidic catalyst selected from the groupconsisting of hydrogen chloride gas, hydrochloric acid, sulfuric acid,and acetic acid.
 3. A process for the preparation of a glyoxal-2-oximderivative represented by the formula, ##STR9## wherein R representshydrogen, C₁₋₄ alkyl or phenyl, which comprises reacting a compound ofthe formula, ##STR10## wherein R is defined as above, with a compound ofthe formula, R'ONO [IV] wherein R' represents hydrogen or lower alkylselected from the group consisting of methyl, ethyl, propyl, butyl andamyl, at a temperature of -10° C. to 50° C. in the presence of a basiccatalyst selected from the group consisting of sodium methoxide, sodiumethoxide, potassium methoxide and potassium ethoxide.